Cyclopentane heptan(ene)oic acid, 2-heteroarylalkenyl derivatives as therapeutic agents

ABSTRACT

A compound comprising  
                 
or a pharmaceutically acceptable salt or a prodrug thereof, having the groups described in detail herein is disclosed. 
 
Also disclosed herein are compounds comprising  
                 
or derivatives thereof, or pharmaceutically acceptable salts, tetrazoles, or prodrugs of compounds of the structure or derivatives thereof, said derivatives being described in detail herein. Also disclosed herein are methods of treating diseases or conditions, including glaucoma and elevated intraocular pressure. Compositions and methods of manufacturing medicaments related thereto are also disclosed.

FIELD OF THE INVENTION

This invention relates to compounds which are useful as therapeuticagents. Among other potential uses, these compounds are believed to haveproperties which are characteristic of prostaglandins.

BACKGROUND OF THE INVENTION DESCRIPTION OF RELATED ART

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives have been reported to possessocular hypotensive activity, and have been recommended for use inglaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

Prostaglandins were earlier regarded as potent ocular hypertensives,however, evidence accumulated in the last decade shows that someprostaglandins are highly effective ocular hypotensive agents, and areideally suited for the long-term medical management of glaucoma (see,for example, Bito, L. Z. Biological Protection with Prostaglandins,Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252;and Bito, L. Z., Applied Pharmacology in the Medical Treatment ofGlaucomas Drance, S. M. and Neufeld, A. H. eds., New York, Grune &Stratton, 1984, pp. 477-505. Such prostaglandins include PGF_(2α),PGF_(1β), PGE₂, and certain lipid-soluble esters, such as C₁ to C₂ alkylesters, e.g. 1-isopropyl ester, of such compounds.

Although the precise mechanism is not yet known experimental resultsindicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et. al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

The isopropyl ester of PGF_(2α) has been shown to have significantlygreater hypotensive potency than the parent compound, presumably as aresult of its more effective penetration through the cornea. In 1987,this compound was described as “the most potent ocular hypotensive agentever reported” [see, for example, Bito, L. Z., Arch. Ophthalmol. 105,1036 (1987), and Siebold et al., Prodrug 5 3 (1989)].

Whereas prostaglandins appear to be devoid of significant intraocularside effects, ocular surface (conjunctival) hyperemia and foreign-bodysensation have been consistently associated with the topical ocular useof such compounds, in particular PGF_(2α) and its prodrugs, e.g., its1-isopropyl ester, in humans. The clinical potentials of prostaglandinsin the management of conditions associated with increased ocularpressure, e.g. glaucoma are greatly limited by these side effects.

In a series of United States patents assigned to Allergan, Inc.prostaglandin esters with increased ocular hypotensive activityaccompanied with no or substantially reduced side-effects are disclosed.Some representative examples are U.S. Pat. No. 5,446,041, U.S. Pat. No.4,994,274, U.S. Pat. No. 5,028,624 and U.S. Pat. No. 5,034,413 all ofwhich are hereby expressly incorporated by reference.

GB 1,601,994 discloses compounds having the formula shown below

in which A represents a CH═CH group; B represents a-CH2-CH2- ,trans-CH═CH— or —C≡C— group, W represents a free, esterified oretherified hydroxymethylene group, wherein the hydroxy or esterified oretherified hydroxy group is in the- or A-configuration, . . . or Wrepresents a free or ketalised carbonyl group, D and E togetherrepresent a direct bond, or D represents an alkylene group having from 1to 5 carbon atoms or a —C≡C— group, and E represents an oxygen orsulphur atom or a direct bond, R₃ represents an aliphatic hydrocarbonradical, preferably an alkyl group, which may be unsubstituted orsubstituted by a cycloalkyl, alkyl substituted cycloalkyl, unsubstitutedor substituted aryl or heterocyclic group, a cycloalkyl oralkyl-substituted cycloalkyl group, or an unsubstituted or substitutedaryl or heterocyclic group, e.g. a benzodioxol-2-yl group, and Zrepresents a free or ketalised carbonyl group or a free esterified oretherified hydroxymethylene group in which the free, esterified oretherified hydroxy group may be in the α or β-configuration.

JP 53135955 discloses several compounds such as the one shown below.

DE 2719244 discloses several compounds such as the ones shown below.

For the top compound (I), R═H, C₁₋₄ alkyl, or H₂HC(CH₂OH)₃; R¹, R²═H orMe; and R³=a heterocycle (often substituted).

U.S. Pat. No. 4,055,602 discloses several compounds such as the oneshown below,

wherein n=2-4; R═H or OH; R¹, R²═H, F, Me; and Ar=aryl. The '602 patentalso discloses the compound shown below, and others like it.

DE 2626888 discloses several compounds such as the one shown below.

Also disclosed herein are compounds having an α and an ω chaincomprising

or a derivative thereof, wherein said derivative has a structure asshown above except that 1 or 2 alterations are made to the α chainand/or the ω chain, and wherein an alteration consists of:

-   -   a. adding, removed, or substituting a non-hydrogen atom, or    -   b. changing the bond order of an existing covalent bond without        adding or deleting said bond;        or a pharmaceutically acceptable salt, a tetrazole, or a prodrug        thereof.

Also disclosed herein are methods of treating diseases or conditions,including glaucoma and elevated intraocular pressure. Compositions andmethods of manufacturing medicaments related thereto are also disclosed.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

FIGS. 1 and 2 illustrate one method of preparing the compounds disclosedherein.

DETAILED DESCRIPTION OF THE INVENTION

A person of ordinary skill in the art understands the meaning of thestereochemistry associated with the hatched wedge/solid wedge structuralfeatures. For example, an introductory organic chemistry textbook(Francis A. Carey, Organic Chemistry, New York: McGraw-Hill Book Company1987, p. 63) states “a wedge indicates a bond coming from the plane ofthe paper toward the viewer” and the hatched wedge, indicated as a“dashed line”, “represents a bond receding from the viewer.”

In relation to the identity of A disclosed in the chemical structurespresented herein, in the broadest sense, A is —(CH₂)₆—, or cis—CH₂CH═CH—(CH₂)₃—, wherein 1 or 2 carbons may be substituted with S orO. In other words, A may be —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or A may bea group which is related to one of these two moieties in that any carbonis substituted with S or O. For example, while not intending to limitthe scope of the invention in any way, A may be an S substituted moietysuch as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be an O substituted moiety such as one of thefollowing or the like.

In other embodiments, A is —(CH₂)₆— or cis-CH₂CH═CH—(CH₂)₃— having noheteroatom substitution.

Since J can be —OH or ═O, compounds of the structures shown below arepossible, or pharmaceutically acceptable salts or prodrugs thereof.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions, lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Ester prodrugs of the compounds disclosed herein are specificallycontemplated. While not intending to be limiting, an ester may be analkyl ester, an aryl ester, or a heteroaryl ester. The term alkyl hasthe meaning generally understood by those skilled in the art and refersto linear, branched, or cyclic alkyl moieties. C₁₋₆ alkyl esters areparticularly useful, where alkyl part of the ester has from 1 to 6carbon atoms and includes, but is not limited to, methyl, ethyl, propyl,isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl isomers, hexylisomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcombinations thereof having from 1-6 carbon atoms, etc.

A “tetrazole” as disclosed herein is meant to be a compound wherein acarboxylic acid is substituted with a tetrazole functional group. Thus,a tetrazole of a compound of the structure

would have the structure shown below.

Tetrazoles are known in the art to be interchangeable with carboxylicacids in biological systems. In other words, if a compound comprising acarboxylic acid is substituted with a tetrazole, it is expected that thecompound would have similar biological activity. A pharmaceuticallyacceptable salt or a prodrug of a tetrazole is also considered to be atetrazole for the purposes of this disclosure.

Another embodiment comprises

or a pharmaceutically acceptable salt, a tetrazole, or a prodrugthereof. In other embodiments, the compound is the acid or apharmaceutically acceptable salt, and not a tetrazole or a prodrug.

Another embodiment comprises

or a pharmaceutically acceptable salt, a tetrazole, or a prodrugthereof. In other embodiments, the compound is the acid or apharmaceutically acceptable salt, and not a tetrazole or a prodrug.

One embodiment comprises derivatives of

wherein said derivative has a structure as shown above except that 1 or2 alterations are made to the α chain and/or the ω chain, wherein analteration consists of 1) adding, removed, or substituting anon-hydrogen atom, or 2) changing the bond order of an existing covalentbond without adding or deleting said bond. Salts, tetrazoles, andprodrugs of the depicted compound or derivatives thereof are alsocontemplated.

Thus, a compound having the structure above is contemplated, as well asa pharmaceutically acceptable salt a prodrug, or a tetrazole thereof.

In making reference to a derivative and alterations to a structure asshown above, it should be emphasized that making alterations and formingderivatives is strictly a mental exercise used to define a set ofchemical compounds, and has nothing to do with whether said alterationcan actually be carried out in the laboratory, or whether a derivativecan be prepared by an alteration described. However, whether thederivative can be prepared via any designated alteration or not, thedifferences between the derivatives and the aforementioned structure aresuch that a person of ordinary skill in the art could prepare thederivatives disclosed herein using routine methods known in the artwithout undue experimentation.

The α chain is the group in the solid circle in the labeled structureabove. The ω chain is the group in the dashed circle in the labeledstructure above. Thus, in these embodiments said derivative may bedifferent from the formula above at the α chain, while no alteration ismade to the ω chain, as for example, in the structures shown below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

The derivatives may also be different from the formula above in the ωchain, while no alteration is made to the α chain, as shown in theexamples below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Alternatively, the derivatives may be different in both the α and ωchains, as shown in the examples below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Changes to the structure can take several forms, if a non-hydrogen atomis added, the structure is changed by adding the atom, and any requiredhydrogens, but leaving the remaining non-hydrogen atoms unchanged, suchas in the two examples shown below, with the added atoms in bold type.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

If a non-hydrogen atom is removed, the structure is changed by removingthe atom, and any required hydrogens, but leaving the remainingnon-hydrogen atoms unchanged, such as in the two examples shown below,with the previous location of the missing atoms indicated by arrows.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

If a non-hydrogen atom is substituted, the non-hydrogen atom is replacedby a different non-hydrogen atom, with any necessary adjustment made tothe number of hydrogen atoms, such as in the two examples shown below,with the substituted atoms in bold type.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Changing the bond order of an existing covalent bond without adding ordeleting said bond refers to the changing of a single bond to a doubleor triple bond, changing a double bond to a single bond or a triplebond, or changing a triple bond to a double or a single bond. Adding ordeleting a bond, such as occurs when an atom is added, deleted, orsubstituted, is not an additional alteration for the purposes disclosedherein, but the addition, deletion, or substitution of the non-hydrogenatom, and the accompanying changes in bonding are considered to be onealteration. Three examples of this type of alteration are shown below,with the top two examples showing alteration in the double bond of the αchain, and the bottom example showing alteration in the C—O single bondof the ω chain.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

If a derivative could reasonably be construed to consist of a differentnumber of alterations, the derivative is considered to have the lowestreasonable number of alterations. For example, the compound shown below,having the modified portion of the molecule in bold, could be reasonablyconstrued to have 1 or 2 alterations relative to the defined structure.

By one line of reasoning, the first alteration would be to remove thehydroxyl group from the carboxylic acid functional group, yielding analdehyde. The second alteration would be to change the C═O double bondto a single bond, yielding the alcohol derivative shown above. By asecond line of reasoning, the derivative would be obtained by simplyremoving the carbonyl oxygen of the carboxylic acid to yield thealcohol. In accordance with the rule established above, the compoundabove is defined as having 1 alteration. Thus, an additional alterationcould be made to the structure to obtain the compounds such as theexamples shown below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

In one embodiment, O or S is substituted for CH₂, as seen in several ofthe examples disclosed previously herein, as well as in the examplesbelow.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Certain compounds comprise C═O, i.e. the bond order of the C—O bond isincreased from a single to double bond as in the compounds shown below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Other embodiments comprise no Br, i.e. it is removed or another atom issubstituted for it, as in the examples shown below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Other embodiments comprise no CH₃, i.e. it is removed or another atom issubstituted for it, as in the examples shown below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

In many embodiments, the compound comprises a thienyl or substitutedthienyl moiety. A number of examples of these compounds are given above.However, certain embodiments may have a substituted furyl, phenyl, orother aromatic moiety, such as the examples shown below.

Pharmaceutically acceptable salts, tetrazoles, and prodrugs of thesecompounds are also contemplated.

Another embodiment comprises(Z)-7-{(1R,2R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-hydroxy-pent-1-enyl]-5-hydroxy-cyclopentyl}-hept-5-enoicacid.

The compounds of disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administeredis, of course, dependent on the therapeutic effect or effects desired,on the specific mammal being treated, on the severity and nature of themammal's condition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds ispreferably in the range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric, acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts: IngredientAmount (% w/v) active ingredient about 0.001-5 preservative 0-0.10vehicle 0-40 tonicity adjustor 1-10 buffer 0.01-10 pH adjustor q.s. pH4.5-7.5 antioxidant as needed surfactant as needed purified water asneeded to make 100%

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

EXAMPLE 1

Compounds of Table 1 were prepared according to the followingprocedures.

Compound 1 was prepared by methods disclosed in U.S. Pat. No. 6,124,344,incorporated by reference herein.

(Z)-7-[(1R,2R,3R,5S)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-(tetrahydro-pyran-2-yloxy)-pent-1-enyl]-3,5-bis-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-hept-5-enoicacid methyl ester (2). An acetone (24 mL) solution of acid 1 was treatedwith DBU (1.4 mL, 9.36 mmol) and methyl iodide (0.6 mL, 9.63 mmol). Thereaction was stirred for 21 h and then 50 mL 1 M HCl was added and themixture extracted with ethyl acetate (3×50 mL). The combined ethylacetate solution was dried (Na₂SO₄), filtered and evaporated to leave abrown oil that was used directly in the next step.

(Z)-7-{(1R,2R,3R,5S)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-hydroxy-pent-1-enyl]-3,5-dihydroxy-cyclopentyl}-hept-5-enoicacid methyl ester (3). A mixture of the crude ester (2) in methanol (16mL) was treated with pyridinium p-toluenesulfonate (2.625 g, 10.4 mmol).After 21 h, the solvent was evaporated in vacuo and the residue purifiedby flash chromatography on silica gel (90% ethyl acetate/hexanes→95%) togive 3 (3.453 g, 6.9 mmol, 86% for the two steps).

(Z)-7-[(1R,2R,3R,5S)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-(tert-butyl-dimethyl-silanyloxy)-pent-1-enyl]-3-(tert-butyl-dimethyl-silanyloxy)-5-hydroxy-cyclopentyl]-hept-5-enoicacid methyl ester (4). A dichloromethane (14 mL) solution of 3 (3.452 g,6.9 mmol) was treated with triethylamine (2.9 mL, 20.8 mmol), DMAP (211mg, 1.73 mmol) and TBSCl (2.130 g, 14.1 mmol). The reaction was allowedto stir for 22 h and then was quenched by addition of 100 mL saturatedNaHCO₃ solution. The mixture was extracted with CH₂Cl₂ (3×75 mL) and thecombined CH₂Cl₂ solution was dried (Na₂SO₄), filtered and evaporated.Purification by flash chromatography (10% ethyl acetate/hexane→20%) gave4 (3.591 g, 4.9 mmol, 71%).

(Z)-7-[(1R,2R,3R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-(tert-butyl-dimethyl-silanyloxy)-pent-1-enyl]-3-(tert-butyl-dimethyl-silanyloxy)-5-oxo-cyclopentyl]-hept-5-enoicacid methyl ester ( 5). A mixture of alcohol 4 (3.591 g, 4.9 mmol), 4Amolecular sieves (2.5 g), and NMO (867 mg, 7.4 mmol) in dichloromethane(10 mL) was treated with TPAP (117 mg, 0.33 mmol). After 1 h, themixture was filtered through celite and the filtrate evaporated invacuo. Purification by flash chromatography (5% ethylacetate/hexanes→7.5%) gave 5 (2.984 g, 4.1 mmol, 84%).

(Z)-7-{(1R,2S)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-hydroxy-pent-1-enyl]-5-oxo-cyclopent-3-enyl}-hept-5-enoicacid methyl ester (6). A mixture of 5 (1.486 g, 2.03 mmol), HOAc (20mL), H₂O (10 mL) and THF (10 mL) was stirred at 70° C. for 17 h. Thereaction was then poured into 750 mL saturated NaHCO₃ solution and theresulting mixture was extracted with ethyl acetate (4×200 mL). Thecombined ethyl acetate solution was dried (Na₂SO₄), filtered andevaporated. Flash chromatography (50% ethyl acetate/hexanes) gave 6 (497mg, 1.03 mmol, 51%).

(Z)-7-{(1R,2S)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-(tert-butyl-dimethyl-silanyloxy)-pent-1-enyl]-5-oxo-cyclopent-3-enyl}-hept-5-enoicacid methyl ester (7). A dichloromethane (6 mL) solution of 6 (497 mg,1.03 mmol) was treated with 2,6-lutidine (143 μL, 1.22 mmol) and TBSOTf(0.26 mL, 1.13 mmol). After 1.5 h, 50 mL saturated NaHCO₃ was added andthe resulting mixture was extracted with 25 mL CH₂Cl₂. The CH₂Cl₂ layerwas washed with 50 mL 1 M HCl and 50 mL brine. The CH₂Cl₂ solution wasthen dried (Na₂SO₄), filtered and evaporated. Purification by flashchromatography (8% ethyl acetate/hexanes→10%) gave 7 (553 mg, 0.93 mmol,90%).

(Z)-7-{(1R,2R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-(tert-butyl-dimethyl-silanyloxy)-pent-1-enyl]-5-oxo-cyclopentyl}-hept-5-enoicacid methyl ester (8). A solution of 7 (170 mg, 0.28 mmol) in 4 mLtoluene was added, by cannula, to a −40° C. mixture ofhydrido(triphenylphosphine)copper(I) hexamer (300 mg, 0.15 mmol) in 4 mLtoluene, rinsing with 0.5 mL toluene. The temperature was allowed towarm to 0° C. over 1 h and then was allowed to warm to room temperature.After a further 1 h, the reaction was quenched by addition of 15 mLsaturated NH₄Cl solution. The mixture was extracted with ethyl acetate(3×15 mL) and the combined ethyl acetate solution was dried (Na₂SO₄),filtered and evaporated. Purification by flash chromatography (8% ethylacetate/hexanes→10%) gave the title ketone (150 mg, 0.25 mmol, 89%).

(Z)-7-{(1R,2R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-(tert-butyl-dimethyl-silanyloxy)-pent-1-enyl]-5-hydroxy-cyclopentyl}-hept-5-enoicacid methyl ester (9H,L). A methanol (0.8 mL) solution of ketone 8 (150mg, 0.25 mmol) was treated with NaBH₄ (15 mg, 0.40 mmol). After 1 h, thereaction was quenched with 15 mL 1 M HCl and the resulting mixture wasextracted with dichloromethane (3×15 mL). The combined dichloromethanesolution was dried (Na₂SO₄), filtered and evaporated to give thealcohols 9H,L which were used directly in the next step.

(Z)-7-{(1R,2R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-hydroxy-pent-1-enyl]-5-hydroxy-cyclopentyl)-hept-5-enoicacid methyl ester (10H,L). A solution of the crude alcohols 9 in HOAc (2mL)/H₂O (1 mL)/THF (1 mL) was heated at 70° C. for 2 h and then wasquenched by addition of 100 mL saturated NaHCO₃ solution. The resultingmixture was extracted with ethyl acetate (4×100 mL) and the combinedethyl acetate solution was dried (Na₂SO₄), filtered and evaporated.Flash chromatography (45% ethyl acetate/hexanes) followed by preparativeTLC (42% ethyl acetate/hexanes) gave the two C9 diastereomers: highR_(f) 29 mg (0.06 mmol, 24% for 2 steps) and low R_(f) 53 mg (0.11 mmol,43%).

(Z)-7-{(1R,2R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-hydroxy-pent-1-enyl]-5-hydroxy-cyclopentyl}-hept-5-enoicacid (11H). A THF (1.3 mL) solution of 10H (27 mg, 0.055 mmol) wastreated with 0.5 M LiOH (0.33 mL, 0.17 mmol). The reaction was allowedto stir for 18 h and then 10 mL 1 M HCl was added. The resulting mixturewas extracted with dichloromethane (3×15 mL) and the combineddichloromethane solution was dried (Na₂SO₄), filtered and evaporated.Purification by flash chromatography (5% methanol/dichloromethane) gave11H (20 mg, 0.042 mmol, 77%). 300 MHz NMR (CDCl₃, ppm) δ 6 6.58 (1 H, s)5.6-5.3 (4 H, overlapping m) 4.3-4.1 (2 H, overlapping m) 2.8-2.7 (2 H,m) 2.32 (3 H, s) 2.4-1.3 (16 H, overlapping m). TABLE 1 FUNCTIONAL DATA(EC5O nm) Rf STRUCTURE HFP HEP1 HEP2 HEP3A HEP4 HTP HIP HDP High

2069 NA NA >10⁵ NA 1868 NA NA Low

NA NA NA NA NA NA NA NA High

>10⁵ NA 793 >10⁵ 96 NA NA Low

>10⁵ NA NA >10⁵ 832 >10⁵ NA NA

EXAMPLE 2

The biological activity of the compounds of Table 1 was tested using thefollowing procedures.

Methods for Flipr™ Studies

(a) Cell Culture

HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP4/Gqs5; hFP;hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

(b) Calcuim Signal Studies on the Flipr™

Cells were seeded at a density of 5×10⁴ cells per well in Biocoat®Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates were washed fourtimes with HBSS-HEPES buffer to remove excess dye leaving 100 μl in eachwell. Plates were re-equilibrated to 37° C. for a few minutes.

Cells were excited with an Argon laser at 488 nm, and emission wasmeasured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50μl volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP_(4/)Gqs5); PGF_(2α) (hFP); carbacyclin(hIP); U-46619 (hTP), depending on receptor). The peak fluorescencechange in each drug-containing well was then expressed relative to thecontrols.

Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n≧3.

The results of the activity studies presented in the table demonstratethat the compounds disclosed herein are prostaglandin receptor agonists,and are thus useful for the treatment of glaucoma, ocular hypertension,the other diseases or conditions related to the activity of theprostaglandin receptors.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound having an α and an ω chain comprising

or a derivative thereof, wherein said derivative has a structure asshown above except that 1 or 2 alterations are made to the a chainand/or the co chain, and wherein an alteration consists of: a. adding,removed, or substituting a non-hydrogen atom, or b. changing the bondorder of an existing covalent bond without adding or deleting said bond;or a pharmaceutically acceptable salt, a tetrazole, or a prodrugthereof.
 2. The compound of claim 1 wherein O or S is substituted forCH₂.
 3. The compound of claim 1 comprising C═O.
 4. The compound of claim1 having the same α chain as said structure.
 5. The compound of claim 1having the same ω chain as said structure.
 6. The compound of claim 1comprising a thienyl or a substituted thienyl moiety.
 7. The compound ofclaim 1 having no Br.
 8. The compound of claim 1 having no CH₃.
 9. Thecompound of claim 1 having 1 alteration.
 10. A compound comprising

or a pharmaceutically acceptable salt, or a prodrug thereof; wherein thedashed line indicates the presence or absence of a bond; A is —(CH₂)₆—,or cis —CH₂—CH═CH—(CH₂)₃—, wherein 1 or 2 carbons may be substitutedwith S or O; J is —OH or ═O; or a pharmaceutically acceptable salt or aprodrug thereof.
 11. The compound of claim 11 comprising

or a pharmaceutically acceptable salt, or a prodrug thereof.
 12. Thecompound of claim 11 comprising

or a pharmaceutically acceptable salt, or a prodrug thereof.
 13. Thecompound of claim 11 comprising

or a pharmaceutically acceptable salt or a prodrug thereof.
 14. Acomposition comprising a compound having an α and an ω chain comprising

or a derivative thereof, wherein said derivative has a structure asshown above except that 1 or 2 alterations are made to the α chainand/or the ω chain, and wherein an alteration consists of: a. adding,removed, or substituting a non-hydrogen atom, or b. changing the bondorder of an existing covalent bond without adding or deleting said bond;or a pharmaceutically acceptable salt, a tetrazole, or a prodrugthereof; and wherein said composition is a liquid which is suitable forophthalmic administration.
 15. A method comprising administering atherapeutically active agent to a mammal, said method being effectivefor the reduction of intraocular pressure, said therapeutically activeagent comprising

or a pharmaceutically acceptable salt, or a prodrug thereof; wherein thedashed line indicates the presence or absence of a bond; A is —(CH₂)₆—,or cis —CH₂—CH═CH—(CH₂)₃—, wherein 1 or 2 carbons may be substitutedwith S or O; J is —OH or ═O; or a pharmaceutically acceptable salt or aprodrug thereof.
 16. The compound of claim 1 comprising(Z)-7-{(1R,2R)-2-[(E)-(S)-5-(4-Bromo-5-methyl-thiophen-2-yl)-3-hydroxy-pent-1-enyl]-5-hydroxy-cyclopentyl}-hept-5-enoicacid.